Crystalline forms of atorvastatin

ABSTRACT

The present invention is directed to new crystalline forms of Atorvastatin calcium (2:1), referred to hereinafter as polymorphic Forms X, A, B1, B2, C, D and E. The present invention also is directed to crystalline Form A of Atorvastatin calcium (2:1) that is stable against the formation of the AED impurity. Furthermore, the present invention is directed to processes for the preparation of these crystalline forms and pharmaceutical compositions comprising the crystalline forms.

This application is a continuation of U.S. patent application Ser. No.10/130,197, which in turn is the U.S. national Stage application under35 U.S.C.§371 of International Patent Application No.PCT/EP01/15012,having an international filing date of Dec. 19, 2001, and claimspriority under 35 U.S.C. § 119 from European Patent Application No.00811249.2, filed Dec. 27, 2000; the disclosures of the above beingincorporated by reference in their entirety.

The present invention is directed to crystalline forms of Atorvastatincalcium, processes for their preparation and pharmaceutical compositionscomprising these crystalline forms.

The present invention relates to crystalline forms of Atorvastatincalcium. Atorvastatin calcium is known by the chemical name,[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt (2:1). Atorvastatin has the following formula:

Atorvastatin calcium is an orally-active hypocholesterolaernic, aher-selective HMG-CoA reductase inhibitor. Processes for the preparationof Atorvastatin calcium are described in U.S. Pat. No. 5,298,627, U.S.Pat. No. 5,273,995 and WO-A-97/03960, and publications by P. L. Broweret al. in Tetrahedron Letters (1992), vol. 33, pages 2279-2282, K. L.Baumann et al. in Tetrahedron Letters (1992), vol. 33, pages 2283-2284and A. Graul et al. in Drugs Future (1997), vol. 22, pages 956-968.

This calcium salt (2:1) is desirable since it enables Atorvastatincalcium to be conveniently formulated. The processes in the abovementioned patents and publications result in the preparation ofamorphous Atorvastatin calcium.

The preparations of Atorvastatin calcium (2:1) described inWO-A-97/03958 and WO-A-97103959 result in the isolation of crystallineAtorvastatin calcium with the polymorphic forms III, and I, II, and IV,respectively. However, there is still a need to produce Atorvastatincalcium in a reproducible, pure and crystalline form to enableformulations to meet exacting pharmaceutical requirements andspecifications. Furthermore, it is economically desirable that theproduct is stable for extended periods of time without the need forspecialized Storage conditions.

Surprisingly, there have now been found several novel crystalline formsof Atorvastatin calcium salt (2:1), herein designated as Form X, Form A,Form B1, Form B2, Form C, Form D and Form E. The novel forms of thepresent invention have a good thermal stability and/or good solubilitycharacteristics.

Like any synthetic compound, Atorvastatin hemi-calcium salts can containextraneous compounds or impurities that can come from many sources. Theycan be unreacted starting materials, by-products of the reaction,products of side reactions, or degradation products. Impurities inatorvastatin hemi-calcium salts or any active pharmaceutical ingredient(API) are undesirable and, in extreme cases, might even be harmful to apatient being treated with a dosage form containing the API.

It is known in the art that impurities in an API may arise fromdegradation of the API itself, which is related to the stability of thepure API during storage. A particular degradation product ofatorvastatin hemi-calcium is atorvastatin calcium epoxy dihydroxy (AED),having the formula:

AED may be characterized by data selected from: ¹H NMR spectrum havinghydrogen chemical shifts at about 1.20, 1.21, 2.37, 4.310, 6.032, 7.00,7.06-7.29, 7.30, 7.39, 7.41, 7.56 ppm; a ¹³C NMR spectrum having carbonchemical shifts at about 16.97, 34.66, 103.49, 106.66, 114.72, 120.59,125.79, 128.21, 128.55, 128.74, 129.06, 129.57, 132.38, 132.51, 135.15,161.61, 163.23 ppm ; an MS (ESI⁺) spectrum having peaks at about having:m/z═472(MNa)⁺, 454 (MNa-H₂O)⁺, 432(MH-H₂O)⁺; 344 (FPhCOC(Ph)═C-CONHPh)⁺by retention time of about 32 min and by a relative retention time ofabout 1.88, in HPLC analysis such as described in U.S. patentapplication Ser. No. 11/236,647 and International Patent ApplicationPCT/US05/35159.

Accordingly, the present invention is directed to the followingpolymorphic Forms X, A, B1, B2, C, D and E of Atorvastatin calcium salt(2: 1).

A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at 27.9 (s), 20.9 (w), 18.9 (w), 16.1 (w), 11.1 (m), 10.5 (m), 9.1 (m),5.53 (m), 5.07 (w), 4.77 (vw), 4.55 (m), 4.13 (w), 3.69 (w); hereindesignated as Form X. Here and in the following the abbreviations inbrackets mean: (vs)=very strong intensity; (s)=strong intensity;(m)=medium intensity; (w)=weak intensity; (W)=very weak intensity.

A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at 31.0 (w), 18.6 (m), 17.0 (w), 15.3(vw), 12.8(w), 11.2(m), 9.6 (s),9.3 (w), 8.6 (w), 7.4(m), 6.5 (vw), 6.2 (w), 5.47 (w), 5.21 (m), 4.64(vs), 4.46 (s), 4.14 (m), 3.97 (m), 3.74 (m), 3.62 (vw), 3.38 (w), 3.10(m), herein designated as Form A.

Furthermore, the present invention is directed to atorvastatinhemi-calcium crystalline Form A, that is stable against the formation ofthe impurity AED.

As used herein, the term “stable” in reference to Atorvastatinhemi-calcium Form A relates to the formation of at least about 0.01%(w/w) of the impurity AED. The stability of Form A is measured bymaintaining Form A at a temperature of about 40° C. at a relativehumidity of about 75% for at least about 1 month, or at a temperature ofabout 25° C. at a relative humidity of about 60% for at least about 6months. Stable Atorvastatin hemi-calcium Form A is a Form A in which nomore than about 0.01% (w/w) of the AED impurity is formed whenmaintained under the conditions specified above.

A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at 27.9 (m), 17.0 (m), 14.2 (w), 12.1 (vs), 10.1 (s), 8.6 (m), 7.1 (m),6.1 (w), 5.27 (m). 4.89 (rn), 4.68 (m), 4.46 (m), 4.22 (m), 3.90 (w),3.70 (w), 2.36 (vw), herein designated as Form B1.

A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at 28.1 (m), 17.2 (m), 14.0 (w), 12.3 (s), 10.4 (s), 8.6 (m), 7.5 (w),7.0 (m), 5.28 (m), 4.88 (m), 4.55 (m), 4.27 (m), 3.88 (w), 3.73 (m),herein designated as Form B2.

A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at 28.8 (m), 24.0 (m), 17.1 (m), 11.3 (s), 9.8 (w). 8.3 (w), 7.7 (w),6.9 (vw), 5.64 (w), 5.21 (w), 4.59 (m), 4.39 (w), 4.16 (w), 3.70 (w),herein designated as Form C.

A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (A)at 33.7 (w), 31.0 (m), 16.9 (m), 10.3 (s), 7.7 (w), 6.4 (w), 4.84 (s),herein designated as Form D.

A crystalline polymorph of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt which exhibits a characteristic X-ray powderdiffraction pattern with characteristic peaks expressed in d-values (Å)at 26.8 (s), 9.4 (w), 4.6 (m) herein designated as Form E.

A discussion of the theory of X-ray powder diffraction patterns can befound in “X-ray diffraction procedures” by H. P. Klug and L. E.Alexander, J. Wiley, New York (1974).

Furthermore, the present invention is directed to processes for thepreparation of Form X, Form A Form B 1, Form B2, Form C, Form D and FormE.

Form X can generally be prepared by drying of a solution of Atorvastatincalcium in an organic solvent. Examples of such organic solvents arealcohols, like methanol. Preferably, the solution in addition containsan organic non-solvent, like ethers, for example methyl tert-butylether. Drying can be carried out at elevated temperature, or,preferably, at ambient temperature. If desired, during the preparationprocess seeding with Form X can be carried out.

Form A can generally be prepared by suspending Form X or the amorphousform in an organic solvent, like an alcohol, especially isopropanol. Itis preferred that the organic solvent contains as a further solvent somewater. The amount of water is preferably about 0.1 to 5%, preferablyabout 0.5 to 2%, especially about I % by volume of the suspension. It ispreferred that the suspension is treated at temperatures between 10 and60° C. (preferably 30 to 50° C.), especially for a longer period oftime, like 10 to 40 hours. If desired, during the preparation processseeding with Form A can be carried out.

Form A can also be prepared from Atorvastatin lactone upon subsequentreaction with NaOH to form Atorvastatin sodium followed by reaction withCaCl₂ in an organic solvent, like an alcohol, especially isopropanol. Itis preferred that the organic solvent contains as a further solvent somewater. The amount of water is preferably 0.1 to 10%. If desired, duringthe preparation process seeding with Form A can be carried out.

Form A can also be prepared directly from Atorvastatin lactone uponreaction with Ca(OH)₂ in an organic solvent, like an alcohol, especiallyisopropanol. It is preferred that the organic solvent contains as afurther solvent some water. The amount of water is preferably 0.1 to10%. If desired, during the preparation process seeding with Form A canbe carried out.

Form A can also be prepared by the reaction of Atorvastatin ammoniumsalt with Ca(II)-acetate in an organic solvent or a mixture of organicsolvents, preferably a mixture of tert-butyl methyl ether (TBME) andisopropanol. The solid formed in this reaction is isolated by filtrationand than stirred as a suspension in an organic solvent, like an alcohol,especially isopropanol. It is preferred that the organic solventcontains as a further solvent some water.

The amount of water is preferably 0.1 to 10%. It is preferred that thesuspension is treated at temperatures between 10 and 60° C., especiallyfor a longer period of time, like 10 to 60 hours. If desired, during thepreparation process seeding with Form A can be carried out.

Form B 1 can generally be prepared by suspending Form X or the amorphousform in acetonitrile containing a further organic solvent, liketetrahydrofuran. It is preferred that the suspension is treated attemperatures between 10 and 50° C. (preferably ambient temperature),especially for a longer period of time, like 10 to 40 hours. If desired,during the preparation process seeding with Form B 1 can be carried out.

Form B2 can generally be prepared by suspending Form X or the amorphousform in acetonitrile, preferably pure acetonitrile. It is preferred thatthe suspension is treated at temperatures between 10 and 50° C.(preferably 30 to 50° C.), especially for a longer period of time, like10 to 40 hours. If desired, during the preparation process seeding withForm B2 can be carried out.

Form C can generally be prepared by suspending Form X or the amorphousform in a mixture of isopropanol and water, and treating the suspensionat ambient temperature for a longer period of time, like 10 to 40 hours.If desired, during the preparation process seeding with Form C can becarried out.

Form D can generally be prepared by suspending Form X or the amorphousform in a mixture of ethanol and water at temperatures between about 20to 60° C. for a longer period of time, like 10 to 40 hours. If desired,during the preparation process seeding with Form D can be carried out.

Form E can generally be prepared by evaporation of a solution of anyform of Atorvastatin, preferably Form X, in 2-butanone or from solventmixtures of 2-butanone with heptane or ethylacetate or ternary mixturesof 2-butanone, heptane and ethylacetate. Evaporation is preferablycarried out slowly, for example within 10 to 40 hours.

Another object of the present invention are pharmaceutical compositionscomprising an effective amount of crystalline polymorphic Form X, FormA, Form B1, Form B2, Form C, Form D or Form E, and a pharmaceuticallyacceptable carrier.

The polymorphic forms may be used as single components or mixtures.

As to the novel polymorphic forms of Atorvastatin calcium it ispreferred that these contain 25-100% by weight, especially 50-100°/0 byweight, of at least one of the novel forms, based on the total amount ofAtorvastatin calcium. Preferably, such an amount of the novelpolymorphic forms of Atorvastatin calcium is 75-100% by weight,especially 90-100% by weight. Highly preferred is an amount of 95-100%by weight.

The following Examples illustrate the invention in more detail.Temperatures are given in degrees Celsius.

EXAMPLE 1 Preparation of Polymorphic Form X

Atorvastatin calcium Form X is prepared by dissolving 127 mgAtorvastatin calcium in a mixture of 2.0 ml methanol and 6.0 ml methyltert.-butyl ether and drying of the solution at ambient temperature.Form X is characterized by a x-ray powder diffraction pattern as shownin FIG. 1. Differential scanning calorimetry in a closed sample pansealed after equilibrium under dry nitrogen for about 16 hours atambient temperature shows a melting point of 168° C. and an enthalpy offusion of about 27 J/g (see FIG. 6). Form X is stored under normalconditions contains about 4% of water.

EXAMPLE 2 Preparation of Polymorphic Form A

Form A is prepared by suspending 100 mg of Form X in 3.0 ml isopropanoltogether with 50 μl H₂O and stirring of this suspension at 40° C. After9 hours an additional amount of 50 μl of water is added to thesuspension and stirring is continued at 40° C. for another 20 hours. Thesuspension is filtrated and crystalline Form A is obtained. Form A ischaracterized by a x-ray powder diffraction pattern as shown in FIG. 2.The obtained crystalline Form A is stable against the formation of theimpurity AED. Differential scanning calorimetry of Form A in a closedsample pan sealed after equilibration under dry nitrogen for about 16hours at ambient temperature reveals a melting point of 179° C. and anenthalpy of fusion of 53 J/g (see FIG. 6).In the above example it isalso possible to start from the amorphous form of Atorvastatin calciuminstead of Form X.

EXAMPLE 3 Preparation of Polymorphic Form B1

Atorvastatin calcium crystal Form BI is prepared by suspending 145 mg ofAtorvastatin calcium Form X in a mixture of 1.0 ml acetonitrile and 1.0ml of tetrahydrofuran at ambient temperature. While the cap of thereaction vial is left open some of the tetrahydrofuran evaporates whichleads to a slow reduction of the solubility of Atorvastatin calcium inthe system. After 3.5 hours an additional amount of 1.0 ml ofacetonitrile is added to the reaction container and stirring iscontinued for about 15 hours at ambient temperature. After filtration ofthe suspension crystal form B1 is obtained. Form B1 is characterized bya x-ray powder diffraction pattern as shown in FIG. 3. In the aboveexample it is also possible to start from the amorphous form ofAtorvastatin calcium instead of Form X.

EXAMPLE 4 Preparation of Polymorphic Form B2

Form B2 is prepared by suspending 117 mg of Atorvastatin calcium Form Xin 2.0 ml of acetonitrile and stirring this suspension at 40° C. forabout 18 hours. In order to reduce the viscosity of the suspension 1.0ml of acetonitrile is added at ambient temperature to this suspensionafter the end of the crystallization process. The obtained product iscrystal Form B2 which is characterized by an x-ray powder diffractionpattern as shown in FIG. 3. In the above example it is also possible tostart from the amorphous form of Atorvastatin calcium instead of Form X.

EXAMPLE 5 Preparation of Polymorphic Form C

Form C is prepared by suspending 120 mg of Atorvastatin calcium Form Xin a mixture of 3.0 ml isopropanol and 1.0 ml water. After one hour ofstirring at ambient temperature 2.0 ml water are added and stirring iscontinued for 15 hours at the same temperature. After filtration of thesuspension crystal Form C is obtained which is characterized by thex-ray diffraction pattern as shown in FIG. 4. In the above example it isalso possible to start from the amorphous form of Atorvastatin calciuminstead of Form X.

EXAMPLE 6 Preparation of Polymorphic Form D

Form D is prepared by suspending 124 mg of Form X in 3.0 ml of ethanoland by stirring this suspension at ambient temperature. After about 2hours a suspension of high viscosity is obtained and 1.0 ml of water areadded b the suspension, which reduces the viscosity substantially. Afteraddition of water, the temperature is slowly raised to 40° C. andstirring is continued at 40° C. for about 16 hours. After filtration ofthe suspension crystal Form D is obtained which is characterized by thex-ray diffraction pattern as shown in FIG. 5. In the above example it isalso possible to start from the amorphous form of Atorvastatin calciuminstead of Form X.

EXAMPLE 7 Preparation of Polymorphic Form E

60 mg of Atorvastatin Form X are dissolved in 2.0 ml 2-butanone (e.g.Fluka No. 04380) and then 2.0 ml of heptane (e.g. Fluka No. 51745) areadded at ambient temperature. This mixture is heated to 50° C. for a fewminutes until all solid residues are dissolved. The mixture is thenslowly cooled to 5° C. and later equilibrated at ambient temperature. Atambient temperature the solvent is slowly evaporated within about 10 to20 hours. After complete evaporation of the solvent Atorvastatin Form Eis obtained as a solid residue. The x-ray diffraction pattern of Form Eis shown in FIG. 7.

a) Preparation of Atorvastatin lactone III:

Diol acid 1 (5 g, 8.9 mmol) is dissolved in 10.7 ml ethanol and 5.6 ml1.6 M NH₃ in ethanol is added at room temperature. The solution is beingstirred over 15 to 30 minutes and the solvent is subsequently removedunder reduced pressure to give a colorless or slightly beige foam (5.15g, approximately 100% yield).

Ammonium salt II (23.91 g, 41.7 mmol) is dissolved in 115 ml aceticacid. The yellow solution is being stirred at 35° C. for approximately16 h. 200 ml dioxane are added twice and the mixture is beingconcentrated at 40° C. and 35 mbar pressure, respectively. The residueis dissolved in 200 ml TBME and being washing with water and brine anddried over magnesium sulfate. Removal of the solvent affords 21.4 g(approx. 95 % yield) Atorvastatin lacton III.

b) Preparation of Atorvastatin calcium Form A starting from Atorvastatinlactone III:

Lacton III (20.6 g, 38.2 mmol) is dissolved in 757 ml 2-propanol/water(19:1) and 1.41 g (0.5 eq) calcium hydroxide is added. The turbidsolution is stirred at 40° C. for 3 d whereupon the solution turns intoa thick suspension. White crystals of form A are collected by filtrationand being dried at 70° C. and 20 mbar pressure overnight. Yield: 19.0 g,86 %. The obtained crystalline Form A is stable against the formation ofthe impurity AED.

EXAMPLE 9 Preparation of Atorvastatin Calcium Form A Starting fromAtorvastatin Ammonium Salt II:

Ammonium salt II (2 g, 3.5 mmol) is dissolved in 20 ml TBME/isopropanol(1:2) and a solution of calciumacetat hydrate (0.5 eq) is added dropwiseat room temperature. The precipitated calcium salt is collected byfiltration and dried at 70° C. and 20 mbar. (Yield 1.6 g; approx. 80 %.)The obtained powder is subsequently being stirred in 58 ml2-propanol/water (19:1) at 40° C. and seeded with 5 % crystals of formA. After 4 d Atorvastatin Calcium form A can be collected by filtration(yield 1.5 g, 91 %). The obtained crystalline Form A is stable againstthe formation of the impurity AED.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a characteristic X-ray powder diffraction pattern for Form X.

FIG. 2 is a characteristic X-ray powder diffraction pattern for Form A.

FIG. 3 are characteristic X-ray powder diffraction Patterns for Form BIand B2.

FIG. 4 is a characteristic X-ray powder diffraction pattern for Form C.

FIG. 5 is a characteristic X-ray powder diffraction pattern for Form D.

FIG. 6 are characteristic Differential Scanning Calorimetry (DSC) scansof Form A and Form X.

FIG. 7 is a characteristic X-ray powder diffraction Pattern for Form E.

1. A crystalline form of[R-(R*,R*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid calcium salt that has the X-ray powder diffraction pattern withcharacteristic peaks expressed in d-values (Å) at 31.0 (w), 18.6(m),17.0 (w), 15.3 (w), 12.8 (w), 11.2 (m), 9.6 (s), 9.3 (w), 8.6 (w), 7.4(m), 6.5 (vw), 6.2 (w), 5.47 (w), 5.21 (m), 4.64 (vs), 4.46 (s), 4.14(m), 3.97 (m), 3.74 (m), 3.62 (w), 3.38 (w), 3.10 (m); wherein (vs)=verystrong intensity; (s)=strong intensity; (m)=medium intensity; (w)=weakintensity; (w)=very weak intensity.
 2. The crystalline form of claim 1,that is stable against the formation of Atorvastatin calcium epoxydihydroxy (AED).
 3. The crystalline form of claim 2, that contains lessthan about 0.01% (w/w) AED after storage at a temperature of about 40°C. at a relative humidity of about 75% for at least about 1 month. 4.The crystalline form of claim 2, that contains less than about 0.01%(w/w) AED after storage at a temperature of about 25° C. at a relativehumidity of about 60% for at least about 6 months.
 5. The crystallineform of atorvastatin hemi-calcium of any one of claims 2 to 4, that isan isopropanolate or an ethanolate.
 6. A process for the preparation ofthe crystalline form according to claim 1, which comprises suspending acrystalline form of Atorvastatin calcium which exhibits a characteristicX-ray powder diffraction pattern with characteristic peaks expressed ind-values (Å) at 27.9 (s), 20.9 (w), 18.9 (w), 16.1 (w), 11.1 (m), 10.5(m), 9.1 (m), 5.53 (m), 5.07 (w), 4.77 (vw), 4.55 (m), 4.13 (w), 3.69(w); or amorphous Atorvastatin calcium in an alcohol containing a smallamount of water and treating the suspension at a temperature between 10and 60° C.
 7. A process for the preparation of the crystalline formaccording to claim 1, which comprises treating a solution ofAtorvastatin lactone in a mixture of isopropanol and water with calciumhydroxide.
 8. A pharmaceutical composition comprising an effectiveamount of the crystalline form according to claim 1, and apharmaceutically acceptable carrier.